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A new ferrocene derivative blocks K-Ras localization and function by oxidative modification at His95
Kristen M Rehl1, Jayaraman Selvakumar2, Rhonda L Pitsch3
1Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
Abstract:
Ras proteins are membrane-bound GTPases that regulate essential cellular processes at the plasma membrane (PM). Constitutively active mutations of K-Ras, one of the three Ras isoforms in mammalian cells, are frequently found in human cancers. Ferrocene derivatives, which elevate cellular reactive oxygen species (ROS), have shown to block the growth of non-small cell lung cancers harboring oncogenic mutant K-Ras. Here, we tested a novel ferrocene derivative on the growth of pancreatic ductal adenocarcinoma and non-small cell lung cancer. Our compound, which elevated cellular ROS levels, inhibited the growth of K-Ras-driven cancers, and abrogated the PM binding and signaling of K-Ras in an isoform-specific manner. These effects were reversed upon antioxidant supplementation, suggesting a ROS-mediated mechanism. We further identified that K-Ras His95 residue plays an important role in this process, and it is putatively oxidized by cellular ROS. Together, our study demonstrates that the redox system directly regulates K-Ras/PM binding and signaling via oxidative modification at the His95, and proposes a role of oncogenic mutant K-Ras in the recently described antioxidant-induced growth and metastasis of K-Ras-driven cancers.
Insights
A novel ferrocene derivative inhibits K-Ras-driven cancers by increasing reactive oxygen species (ROS), blocking K-Ras signaling. Antioxidants reversed these effects, highlighting a ROS-mediated mechanism involving K-Ras His95 oxidation.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ras proteins, including K-Ras, are GTPases regulating cellular processes at the plasma membrane.
- Mutant K-Ras is a driver in many human cancers, including pancreatic and lung cancers.
- Ferrocene derivatives elevate reactive oxygen species (ROS) and inhibit K-Ras-driven cancers.
Purpose of the Study:
- To investigate a novel ferrocene derivative's effect on K-Ras-driven cancers.
- To elucidate the mechanism of action, focusing on ROS and K-Ras/plasma membrane interactions.
- To determine the role of K-Ras His95 in the observed effects.
Main Methods:
- Testing a novel ferrocene derivative on pancreatic ductal adenocarcinoma and non-small cell lung cancer cell lines.
- Measuring cellular ROS levels and K-Ras plasma membrane binding and signaling.
- Evaluating the effects of antioxidant supplementation.
- Site-directed mutagenesis to investigate the role of K-Ras His95.
Main Results:
- The ferrocene derivative inhibited K-Ras-driven cancer growth by elevating ROS levels.
- The compound abrogated K-Ras plasma membrane binding and signaling in an isoform-specific manner.
- These effects were reversible with antioxidants, and K-Ras His95 oxidation was implicated.
Conclusions:
- The study demonstrates ROS-mediated regulation of K-Ras/plasma membrane binding and signaling via His95 oxidation.
- This provides a mechanism for how oncogenic K-Ras contributes to cancer growth and metastasis.
- The findings suggest therapeutic potential for targeting K-Ras in cancers.
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